Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1987 Oct;74:153–168. doi: 10.1289/ehp.8774153

Morphological and behavioral markers of environmentally induced retardation of brain development: an animal model.

J Altman 1
PMCID: PMC1474490  PMID: 3319550

Abstract

In most neurotoxicological studies morphological assessment focuses on pathological effects, like degenerative changes in neuronal perikarya, axonopathy, demyelination, and glial and endothelial cell reactions. Similarly, the assessment of physiological and behavioral effects center on evident neurological symptoms, like EEG and EMG abnormalities, resting and intention tremor, abnormal gait, and abnormal reflexes. This paper reviews briefly another central nervous system target of harmful environmental agents, which results in behavioral abnormalities without any qualitatively evident neuropathology. This is called microneuronal hypoplasia, a retardation of brain development characterized by a quantitative reduction in the normal population of late-generated, short-axoned neurons in specific brain regions. Correlated descriptive and experimental neurogenetic studies in the rat have established that all the cerebellar granule cells and a very high proportion of hippocampal granule cells are produced postnatally, and that focal, low-dose X-irradiation either of the cerebellum or of the hippocampus after birth selectively interferes with the acquisition of the full complement of granule cells (microneuronal hypoplasia). Subsequent behavioral investigations showed that cerebellar microneuronal hypoplasia results in profound hyperactivity without motor abnormalities, while hippocampal microneuronal hypoplasia results in hyperactivity, as well as attentional and learning deficits. There is much indirect clinical evidence that various harmful environmental agents affecting the pregnant mother and/or the infant lead to such childhood disorders as hyperactivity and attentional and learning disorders. As the developing human brain is more mature at birth than the rat brain, the risk for microneuronal hypoplasia and consequent behavioral disorders may be highest at late stages of fetal development, in prematurely born and small-for-weight infants, and during the early stages of infant development. Recent technological advances in brain imaging techniques make it possible to test this hypothesis and to assess the possible relationship between the degree of retarded brain development and ensuing behavioral disorders.

Full text

PDF
153

Images in this article

160FIGURE 9.
on p.160
155FIGURE 2.
on p.155
157FIGURE 5.
on p.157
164FIGURE 14. A
on p.164
164FIGURE 14. B
on p.164
164FIGURE 14. C
on p.164

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aitkin L. M., Boyd J. Responses of single units in cerebellar vermis of the cat to monaural and binaural stimuli. J Neurophysiol. 1975 Mar;38(2):418–429. doi: 10.1152/jn.1975.38.2.418. [DOI] [PubMed] [Google Scholar]
  2. Alfano D. P., Petit T. L. Behavioral effects of postnatal lead exposure: possible relationship to hippocampal dysfunction. Behav Neural Biol. 1981 Jul;32(3):319–333. doi: 10.1016/s0163-1047(81)92372-4. [DOI] [PubMed] [Google Scholar]
  3. Altman J., Anderson W. J. Experimental reorganization of the cerebellar cortex. II. Effects of elimination of most microneurons with prolonged x-irradiation started at four days. J Comp Neurol. 1973 May 15;149(2):123–152. doi: 10.1002/cne.901490202. [DOI] [PubMed] [Google Scholar]
  4. Altman J., Anderson W. J., Strop M. Retardation of cerebellar and motor development by focal x-irradiation during infancy. Physiol Behav. 1971 Aug;7(2):143–150. doi: 10.1016/0031-9384(71)90274-5. [DOI] [PubMed] [Google Scholar]
  5. Altman J., Anderson W. J., Wright K. A. Early effects of x-irradiation of the cerebellum in infant rats: decimation and reconstitution of the external granular layer. Exp Neurol. 1969 Jun;24(2):196–216. doi: 10.1016/0014-4886(69)90015-6. [DOI] [PubMed] [Google Scholar]
  6. Altman J. Autoradiographic and histological studies of postnatal neurogenesis. 3. Dating the time of production and onset of differentiation of cerebellar microneurons in rats. J Comp Neurol. 1969 Jul;136(3):269–293. doi: 10.1002/cne.901360303. [DOI] [PubMed] [Google Scholar]
  7. Altman J., Bayer S. A. Embryonic development of the rat cerebellum. I. Delineation of the cerebellar primordium and early cell movements. J Comp Neurol. 1985 Jan 1;231(1):1–26. doi: 10.1002/cne.902310103. [DOI] [PubMed] [Google Scholar]
  8. Altman J., Bayer S. A. Embryonic development of the rat cerebellum. II. Translocation and regional distribution of the deep neurons. J Comp Neurol. 1985 Jan 1;231(1):27–41. doi: 10.1002/cne.902310104. [DOI] [PubMed] [Google Scholar]
  9. Altman J., Bayer S. A. Prenatal development of the cerebellar system in the rat. I. Cytogenesis and histogenesis of the deep nuclei and the cortex of the cerebellum. J Comp Neurol. 1978 May 1;179(1):23–48. doi: 10.1002/cne.901790104. [DOI] [PubMed] [Google Scholar]
  10. Altman J., Das G. D. Post-natal origin of microneurones in the rat brain. Nature. 1965 Aug 28;207(5000):953–956. doi: 10.1038/207953a0. [DOI] [PubMed] [Google Scholar]
  11. Altman J. Experimental reorganization of the cerebellar cortes. V. Effects of early x-irradiation schedules that allow or prevent the acquisition of basket cells. J Comp Neurol. 1976 Jan 1;165(1):31–47. doi: 10.1002/cne.901650104. [DOI] [PubMed] [Google Scholar]
  12. Altman J. Experimental reorganization of the cerebellar cortex. VII. Effects of late x-irradiation schedules that interfere with cell acquisition after stellate cells are formed. J Comp Neurol. 1976 Jan 1;165(1):65–75. doi: 10.1002/cne.901650106. [DOI] [PubMed] [Google Scholar]
  13. Altman J. Postnatal development of the cerebellar cortex in the rat. I. The external germinal layer and the transitional molecular layer. J Comp Neurol. 1972 Jul;145(3):353–397. doi: 10.1002/cne.901450305. [DOI] [PubMed] [Google Scholar]
  14. Anderson W. J., Altman J. Retardation of cerebellar and motor development in rats by focal X-irradiation beginning at four days. Physiol Behav. 1972 Jan;8(1):57–67. doi: 10.1016/0031-9384(72)90130-8. [DOI] [PubMed] [Google Scholar]
  15. Angevine J. B., Jr, Sidman R. L. Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse. Nature. 1961 Nov 25;192:766–768. doi: 10.1038/192766b0. [DOI] [PubMed] [Google Scholar]
  16. Baver S. A., Altman J. Radiation-induced interference with postnatal hippocampal cytogenesis in rats and its long-term effects on the acquisition of neurons and glia. J Comp Neurol. 1975 Sep;163(1):1–19. doi: 10.1002/cne.901630102. [DOI] [PubMed] [Google Scholar]
  17. Bayer S. A., Altman J. Hippocampal development in the rat: cytogenesis and morphogenesis examined with autoradiography and low-level X-irradiation. J Comp Neurol. 1974 Nov 1;158(1):55–79. doi: 10.1002/cne.901580105. [DOI] [PubMed] [Google Scholar]
  18. Bayer S. A., Brunner R. L., Hine R., Altman J. Behavioural effects of interference with the postnatal acquisition of hippocampal granule cells. Nat New Biol. 1973 Apr 18;242(120):222–224. doi: 10.1038/newbio242222a0. [DOI] [PubMed] [Google Scholar]
  19. Bayer S. A. Development of the hippocampal region in the rat. I. Neurogenesis examined with 3H-thymidine autoradiography. J Comp Neurol. 1980 Mar 1;190(1):87–114. doi: 10.1002/cne.901900107. [DOI] [PubMed] [Google Scholar]
  20. Bayer S. A., Yackel J. W., Puri P. S. Neurons in the rat dentate gyrus granular layer substantially increase during juvenile and adult life. Science. 1982 May 21;216(4548):890–892. doi: 10.1126/science.7079742. [DOI] [PubMed] [Google Scholar]
  21. Brady K., Herrera Y., Zenick H. Influence of parental lead exposure on subsequent learning ability of offspring. Pharmacol Biochem Behav. 1975 Jul-Aug;3(4):561–565. doi: 10.1016/0091-3057(75)90173-2. [DOI] [PubMed] [Google Scholar]
  22. Brown D. R. Neonatal lead exposure in the rat: decreased learning as a function of age and blood lead concentrations. Toxicol Appl Pharmacol. 1975 Jun;32(3):628–637. doi: 10.1016/0041-008x(75)90126-x. [DOI] [PubMed] [Google Scholar]
  23. Butler N. R., Goldstein H. Smoking in pregnancy and subsequent child development. Br Med J. 1973 Dec 8;4(5892):573–575. doi: 10.1136/bmj.4.5892.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Connaughton J. F., Jr, Finnegan L. P., Schut J., Emich J. P. Current concepts in the management of the pregnant opiate addict. Addict Dis. 1975;2(1-2):21–35. [PubMed] [Google Scholar]
  25. DANN M., LEVINE S. Z., NEW E. V. A LONG-TERM FOLLOW-UP STUDY OF SMALL PREMATURE INFANTS. Pediatrics. 1964 Jun;33:945–955. [PubMed] [Google Scholar]
  26. DOUGLAS J. W. Mental ability and school achievement of premature children at 8 years of age. Br Med J. 1956 May 26;1(4977):1210–1214. doi: 10.1136/bmj.1.4977.1210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. David O. J. Association between lower level lead concentrations and hyperactivity in children. Environ Health Perspect. 1974 May;7:17–25. doi: 10.1289/ehp.74717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. David O., Clark J., Voeller K. Lead and hyperactivity. Lancet. 1972 Oct 28;2(7783):900–903. doi: 10.1016/s0140-6736(72)92534-2. [DOI] [PubMed] [Google Scholar]
  29. Davis M. M., Shanks B. Neurological aspects of perinatal narcotic addiction and methadone treatment. Addict Dis. 1975;2(1-2):213–226. [PubMed] [Google Scholar]
  30. Denson R., Nanson J. L., McWatters M. A. Hyperkinesis and maternal smoking. Can Psychiatr Assoc J. 1975 Apr;20(3):183–187. doi: 10.1177/070674377502000302. [DOI] [PubMed] [Google Scholar]
  31. Desmond M. M., Wilson G. S. Neonatal abstinence syndrome: Recognition and diagnosis. Addict Dis. 1975;2(1-2):113–121. [PubMed] [Google Scholar]
  32. Drillien C. M. Aetiology and outcome in low-birthweight infants. Dev Med Child Neurol. 1972 Oct;14(5):563–574. [PubMed] [Google Scholar]
  33. Drillien C. M. Fresh approaches to prospective studies of high risk infants. Pediatrics. 1970 Jan;45(1):7–8. [PubMed] [Google Scholar]
  34. Driscoll J. W., Stegner S. E. Lead-produced changes in the relative rate of open field activity of laboratory rats. Pharmacol Biochem Behav. 1978 Jun;8(6):743–747. doi: 10.1016/0091-3057(78)90276-9. [DOI] [PubMed] [Google Scholar]
  35. Fitzhardinge P. M., Steven E. M. The small-for-date infant. II. Neurological and intellectual sequelae. Pediatrics. 1972 Jul;50(1):50–57. [PubMed] [Google Scholar]
  36. Fricker H. S., Segal S. Narcotic addiction, pregnancy, and the newborn. Am J Dis Child. 1978 Apr;132(4):360–366. doi: 10.1001/archpedi.1978.02120290032004. [DOI] [PubMed] [Google Scholar]
  37. Gazzara R. A., Altman J. Early postnatal x-irradiation of the hippocampus and discrimination learning in adult rats. J Comp Physiol Psychol. 1981 Jun;95(3):484–495. doi: 10.1037/h0077783. [DOI] [PubMed] [Google Scholar]
  38. Goldstein G. W., Asbury A. K., Diamond I. Pathogenesis of lead encephalopathy. Uptake of lead and reaction of brain capillaries. Arch Neurol. 1974 Dec;31(6):382–389. doi: 10.1001/archneur.1974.00490420048005. [DOI] [PubMed] [Google Scholar]
  39. HICKS S. P. Radiation as an experimental tool in mammalian developmental neurology. Physiol Rev. 1958 Jul;38(3):337–356. doi: 10.1152/physrev.1958.38.3.337. [DOI] [PubMed] [Google Scholar]
  40. Hambleton G., Wigglesworth J. S. Origin of intraventricular haemorrhage in the preterm infant. Arch Dis Child. 1976 Sep;51(9):651–659. doi: 10.1136/adc.51.9.651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Huang C. M., Liu G., Huang R. Projections from the cochlear nucleus to the cerebellum. Brain Res. 1982 Jul 22;244(1):1–8. doi: 10.1016/0006-8993(82)90897-6. [DOI] [PubMed] [Google Scholar]
  42. KAWI A. A., PASAMANICK B. Association of factors of pregnancy with reading disorders in childhood. J Am Med Assoc. 1958 Mar 22;166(12):1420–1423. doi: 10.1001/jama.1958.02990120012003. [DOI] [PubMed] [Google Scholar]
  43. KNOBLOCH H., PASAMANICK B. Syndrome of minimal cerebral damage in infancy. J Am Med Assoc. 1959 Jul 18;170(12):1384–1387. doi: 10.1001/jama.1959.03010120020006. [DOI] [PubMed] [Google Scholar]
  44. Kandall S. R., Albin S., Dreyer E., Comstock M., Lowinson J. Differential effects of heroin and methadone on birth weights. Addict Dis. 1975;2(1-2):347–355. [PubMed] [Google Scholar]
  45. Kase M., Noda H., Suzuki D. A., Miller D. C. Target velocity signals of visual tracking in vermal Purkinje cells of the monkey. Science. 1979 Aug 17;205(4407):717–720. doi: 10.1126/science.111350. [DOI] [PubMed] [Google Scholar]
  46. LAUFER M. W., DENHOFF E. Hyperkinetic behavior syndrome in children. J Pediatr. 1957 Apr;50(4):463–474. doi: 10.1016/s0022-3476(57)80257-1. [DOI] [PubMed] [Google Scholar]
  47. LUBCHENCO L. O., HORNER F. A., REED L. H., HIX I. E., Jr, METCALF D., COHIG R., ELLIOTT H. C., BOURG M. Sequelae of premature birth. Evaluation of premature infants of low birth weights at ten years of age. Am J Dis Child. 1963 Jul;106:101–115. [PubMed] [Google Scholar]
  48. Landrigan P. J., Whitworth R. H., Baloh R. W., Staehling N. W., Barthel W. F., Rosenblum B. F. Neuropsychological dysfunction in children with chronic low-level lead absorption. Lancet. 1975 Mar 29;1(7909):708–712. doi: 10.1016/s0140-6736(75)91627-x. [DOI] [PubMed] [Google Scholar]
  49. Naeye R. L., Blanc W., Leblanc W., Khatamee M. A. Fetal complications of maternal heroin addiction: abnormal growth, infections, and episodes of stress. J Pediatr. 1973 Dec;83(6):1055–1061. doi: 10.1016/s0022-3476(73)80550-5. [DOI] [PubMed] [Google Scholar]
  50. Needleman H. L., Gunnoe C., Leviton A., Reed R., Peresie H., Maher C., Barrett P. Deficits in psychologic and classroom performance of children with elevated dentine lead levels. N Engl J Med. 1979 Mar 29;300(13):689–695. doi: 10.1056/NEJM197903293001301. [DOI] [PubMed] [Google Scholar]
  51. Papile L. A., Burstein J., Burstein R., Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978 Apr;92(4):529–534. doi: 10.1016/s0022-3476(78)80282-0. [DOI] [PubMed] [Google Scholar]
  52. Pellegrino L. J., Altman J. Effects of differential interference with postnatal cerebellar neurogenesis on motor performance, activity level, and maze learning of rats: a developmental study. J Comp Physiol Psychol. 1979 Feb;93(1):1–33. doi: 10.1037/h0077589. [DOI] [PubMed] [Google Scholar]
  53. Pentschew A., Garro F. Lead encephalo-myelopathy of the suckling rat and its implications on the porphyrinopathic nervous diseases. With special reference to the permeability disorders of the nervous system's capillaries. Acta Neuropathol. 1966 Jun 1;6(3):266–278. doi: 10.1007/BF00687857. [DOI] [PubMed] [Google Scholar]
  54. Pentschew A. Morphology and morphogenesis of lead encephalopathy. Acta Neuropathol. 1965 Nov 18;5(2):133–160. doi: 10.1007/BF00686515. [DOI] [PubMed] [Google Scholar]
  55. Peters P. J., Brunner R. L. Increased running wheel activity and dyadic behavior of rats with hippocampal granule cell deficits. Behav Biol. 1976 Jan;16(1):91–97. doi: 10.1016/s0091-6773(76)91173-1. [DOI] [PubMed] [Google Scholar]
  56. Petit T. L., Alfano D. P. Differential experience following developmental lead exposure: effects on brain and behavior. Pharmacol Biochem Behav. 1979 Aug;11(2):165–171. doi: 10.1016/0091-3057(79)90009-1. [DOI] [PubMed] [Google Scholar]
  57. Press M. F. Lead encephalopathy in neonatal Long-Evans rats: morphologic studies. J Neuropathol Exp Neurol. 1977 Jan;36(1):169–193. doi: 10.1097/00005072-197701000-00014. [DOI] [PubMed] [Google Scholar]
  58. Ramer C. M., Lodge A. Neonatal addiction: a two-year study. Part I. Clinical and developmental characteristics of infants of mothers on methadone maintenance. Addict Dis. 1975;2(1-2):227–234. [PubMed] [Google Scholar]
  59. Ron S., Robinson D. A. Eye movements evoked by cerebellar stimulation in the alert monkey. J Neurophysiol. 1973 Nov;36(6):1004–1022. doi: 10.1152/jn.1973.36.6.1004. [DOI] [PubMed] [Google Scholar]
  60. Sauerhoff M. W., Michaelson I. A. Hyperactivity and brain catecholamines in lead-exposed developing rats. Science. 1973 Dec 7;182(4116):1022–1024. doi: 10.1126/science.182.4116.1022. [DOI] [PubMed] [Google Scholar]
  61. Silbergeld E. K., Goldberg A. M. Lead-induced behavioral dysfunction: an animal model of hyperactivity. Exp Neurol. 1974 Jan;42(1):146–157. doi: 10.1016/0014-4886(74)90013-2. [DOI] [PubMed] [Google Scholar]
  62. Snowdon C. T. Learning deficits in lead-injected rats. Pharmacol Biochem Behav. 1973 Nov-Dec;1(6):599–604. doi: 10.1016/0091-3057(73)90021-x. [DOI] [PubMed] [Google Scholar]
  63. Sobotka T. J., Cook M. P. Postnatal lead acetate exposure in rats: possible relationship to minimal brain dysfunction. Am J Ment Defic. 1974 Jul;79(1):5–9. [PubMed] [Google Scholar]
  64. Stone M. L., Salerno L. J., Green M., Zelson C. Narcotic addiction in pregnancy. Am J Obstet Gynecol. 1971 Mar 1;109(5):716–723. doi: 10.1016/0002-9378(71)90757-5. [DOI] [PubMed] [Google Scholar]
  65. Suzuki D. A., Noda H., Kase M. Visual and pursuit eye movement-related activity in posterior vermis of monkey cerebellum. J Neurophysiol. 1981 Nov;46(5):1120–1139. doi: 10.1152/jn.1981.46.5.1120. [DOI] [PubMed] [Google Scholar]
  66. THURSTON D. L., MIDDELKAMP J. N., MASON E. The late effects of lead poisoning. J Pediatr. 1955 Oct;47(4):413–423. doi: 10.1016/s0022-3476(55)80052-2. [DOI] [PubMed] [Google Scholar]
  67. Thomas J. A., Dallenbach F. D., Thomas M. The distribution of radioactive lead (210Pb) in the cerebellum of developing rats. J Pathol. 1973 Jan;109(1):45–50. doi: 10.1002/path.1711090106. [DOI] [PubMed] [Google Scholar]
  68. Toews A. D., Kolber A., Hayward J., Krigman M. R., Morell P. Experimental lead encephalopathy in the suckling rat: concentration of lead in cellular fractions enriched in brain capillaries. Brain Res. 1978 May 19;147(1):131–138. doi: 10.1016/0006-8993(78)90777-1. [DOI] [PubMed] [Google Scholar]
  69. Towbin A. Central nervous system damage in the human fetus and newborn infant. Mechanical and hypoxic injury incurred in the fetal-neonatal period. Am J Dis Child. 1970 Jun;119(6):529–542. doi: 10.1001/archpedi.1970.02100050531015. [DOI] [PubMed] [Google Scholar]
  70. Towbin A. Organic causes of minimal brain dysfunction. Perinatal origin of minimal cerebral lesions. JAMA. 1971 Aug 30;217(9):1207–1214. [PubMed] [Google Scholar]
  71. WHITE H. H., FOWLER F. D. Chronic lead encephalopathy. A diagnostic consideration in mental retardation. Pediatrics. 1960 Feb;25:309–315. [PubMed] [Google Scholar]
  72. Wallace R. B., Altman J. Behavioral effects of neonatal irradiation of the cerebellum. I. Qualitative observations in infant and adolescent rats. Dev Psychobiol. 1970;2(4):257–265. doi: 10.1002/dev.420020411. [DOI] [PubMed] [Google Scholar]
  73. Wallace R. B., Altman J. Behavioral effects of neonatal irradiation of the cerebellum. II. Quantitative studies in young-adult and adult rats. Dev Psychobiol. 1970;2(4):266–272. doi: 10.1002/dev.420020412. [DOI] [PubMed] [Google Scholar]
  74. Wiener G., Rider R. V., Oppel W. C., Harper P. A. Correlates of low birth weight. Psychological status at eight to ten years of age. Pediatr Res. 1968 Mar;2(2):110–118. doi: 10.1203/00006450-196803000-00006. [DOI] [PubMed] [Google Scholar]
  75. Wiener G. The relationship of birth weight and length of gestation to intellectual development at ages 8 to 10 years. J Pediatr. 1970 May;76(5):694–699. doi: 10.1016/s0022-3476(70)80286-4. [DOI] [PubMed] [Google Scholar]
  76. Wilson G. S., Desmond M. M., Verniaud W. M. Early development of infants of heroin-addicted mothers. Am J Dis Child. 1973 Oct;126(4):457–462. doi: 10.1001/archpedi.1973.02110190381004. [DOI] [PubMed] [Google Scholar]
  77. Zarkowsky H. S. The lead problem in children: dictum and polemic. Curr Probl Pediatr. 1976 Jul;6(9):1–47. doi: 10.1016/s0045-9380(76)80009-6. [DOI] [PubMed] [Google Scholar]
  78. Zelson C. Infant of the addicted mother. N Engl J Med. 1973 Jun 28;288(26):1393–1395. doi: 10.1056/NEJM197306282882607. [DOI] [PubMed] [Google Scholar]
  79. Zelson C., Rubio E., Wasserman E. Neonatal narcotic addiction: 10 year observation. Pediatrics. 1971 Aug;48(2):178–189. [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES